In the pharmaceutical field, adverse drug reactions (ADRs) are a major clinical concern and are a significant cause of attrition in drug development.
Hepatotoxicity is a particularly prominent cause of drug attrition (1, 2). The metabolism of drugs to chemically reactive metabolites in the liver is an important factor in drug-induced liver injury (DILI) (3, 4). However, the cellular events that link the chemistry of drug bioactivation to the toxicological outcome are poorly understood. A better understanding of the mechanisms and pathways leading to DILI would improve clinical management and inform the design of safer medicines for use in the clinic.
In addition, many drugs can also be toxic to other organs and tissues, such as the skin (irritation, rashes etc.), lungs, kidneys and heart. In severe cases, this may lead to drug attrition or necessitate additional clinical management. A better understanding of the mechanisms and pathways leading to skin, lung, kidney and cardiac toxicity would also be beneficial.
The importance of biomarkers to accelerate the pace of drug development, reduce attrition and to be biologically informative in their own right is becoming generally acknowledged in the pharmaceutical field. The ability to easily detect selective biomarkers of apoptosis, necrosis and inflammation would have immense benefit for differentiating the underlying causes of organ injury, such as drug induced liver, skin, lung, kidney or cardiac injury, and will provide additional information to aid clinical intervention and to inform the development of safer drugs in the future.
There are a few biomarkers that are associated with organ injury, such as, for example, alanine aminotransaminase (ALT), which is associated with liver injury. However, the detection of these biomarkers does not reveal any information about the underlying mechanism or progression of the organ damage.
Accordingly, it is an object of the present invention to provide a simple and convenient approach for detecting and/or assessing drug induced organ or tissue injury, which is also sufficiently sensitive so as to enable the early detection of organ or tissue damage.
It is a further object to provide methodology that enables the underlying mechanisms and pathways contributing to drug-induced organ or tissue injury to be assessed.